Abstract
Background: Pain is a complex polygenic trait whose common genetic underpinnings are relatively ill-defined due in part to challenges in measuring pain as a phenotype. Pain sensitivity can be quantified, but this is difficult to perform at the scale required for genome wide association studies (GWAS). Existing GWAS of pain have identified surprisingly few loci involved in nociceptor function which contrasts strongly with rare monogenic pain states. This suggests a lack of resolution with current techniques. We propose an adaptive methodology within a recall-by-genotype (RbG) framework using detailed phenotyping to screen minor alleles in a candidate ‘nociceptor' gene in an attempt to estimate their genetic contribution to pain.
Methods/Design: Participants of the Avon Longitudinal Study of Parents and Children will be recalled on the basis of genotype at five common non-synonomous SNPs in the ‘nociceptor’ gene transient receptor potential ankylin 1 (TRPA1). Those homozygous for the common alleles at each of the five SNPs will represent a control group. Individuals homozygous for the minor alleles will then be recruited in a series of three sequential test groups. The outcome of a pre-planned early assessment (interim) of the current test group will determine whether to continue recruitment or switch to the next test group. Pain sensitivity will be assessed using quantitative sensory testing (QST) before and after topical application of 10% cinnamaldehyde (a TRPA1 agonist).
Discussion: The design of this adaptive RbG study offers efficiency in the assessment of associations between genetic variation at TRPA1 and detailed pain phenotypes. The possibility to change the test group in response to preliminary data increases the likelihood to observe smaller effect sizes relative to a conventional multi-armed design, as well as reducing futile testing of participants where an effect is unlikely to be observed. This specific adaptive RbG design aims to uncover the influence of common TRPA1 variants on pain sensation but can be applied to any hypothesis-led genotype study where costly and time intensive investigation is required and / or where there is large uncertainty around the expected effect size.
Methods/Design: Participants of the Avon Longitudinal Study of Parents and Children will be recalled on the basis of genotype at five common non-synonomous SNPs in the ‘nociceptor’ gene transient receptor potential ankylin 1 (TRPA1). Those homozygous for the common alleles at each of the five SNPs will represent a control group. Individuals homozygous for the minor alleles will then be recruited in a series of three sequential test groups. The outcome of a pre-planned early assessment (interim) of the current test group will determine whether to continue recruitment or switch to the next test group. Pain sensitivity will be assessed using quantitative sensory testing (QST) before and after topical application of 10% cinnamaldehyde (a TRPA1 agonist).
Discussion: The design of this adaptive RbG study offers efficiency in the assessment of associations between genetic variation at TRPA1 and detailed pain phenotypes. The possibility to change the test group in response to preliminary data increases the likelihood to observe smaller effect sizes relative to a conventional multi-armed design, as well as reducing futile testing of participants where an effect is unlikely to be observed. This specific adaptive RbG design aims to uncover the influence of common TRPA1 variants on pain sensation but can be applied to any hypothesis-led genotype study where costly and time intensive investigation is required and / or where there is large uncertainty around the expected effect size.
| Original language | English |
|---|---|
| Article number | 9 |
| Number of pages | 12 |
| Journal | BMC Medical Genomics |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 12 Jan 2022 |
Bibliographical note
Funding Information:The funding bodies listed below played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. This study is funded by Above and Beyond, the University Hospitals Bristol Charity, via their Neurosciences and Mental Health Legacies Call. Grant reference ABL-2019-20-10 to AEP. The UK Medical Research Council and Wellcome (Grant ref: 21765/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the Authors who serve as guarantors for the contents of this paper. NJT and LJC work in the MRC IEU at the University of Bristol which is supported by the MRC (MC_UU_00011) and the University of Bristol. NJT is a Wellcome Trust Investigator (202802/Z/16/Z) and works within the University of Bristol National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). NJT is supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). LJC is supported by NJT’s Wellcome Trust Investigator grant (202802/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [202802/Z/16/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. JPD is an NIHR Clinical Lecturer in Anaesthesia funded by the University of Bristol and North Bristol Healthcare Trust. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ).
Funding Information:
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.
Publisher Copyright:
© 2022, The Author(s).
Research Groups and Themes
- ALSPAC
Keywords
- ALSPAC
- Recall by Genotype
- Adaptive Design
- Pain
- Quantitative Sensory Testing
- TRPA1